6-O-methyl erythromycin A, of the formula below, is a potent macrolide useful as an antibiotic. ##STR1##
The process of synthesizing 6-O-methyl erythromycin A poses many significant challenges. In particular, the starting material, erythromycin A, is unstable and possesses many functional groups that require protection and deprotection during synthesis. Simple methylation of the 6-position of 2'- and 4"-protected erythromycin A derivatives commonly results in a mixture of methylation products. For this reason, it is difficult to develop an approach to 6-O-methyl erythromycin synthesis that allows for selective methylation at the 6-position and under reaction conditions that are compatible with the survival of erythromycin A.
At present, prior art methods approach this obstacle using a variety of different strategies. Known methods involve many steps of protecting and deprotecting various functional groups of the erythromycin A to achieve selective methylation at the desired 6-position. These strategies involve a multitude different intermediates, many of which are 9-oxime erythromycin A derivatives. Although oxime derivatives provide one useful alternative in the preparation of 6-O-methyl erythromycin, there remains a need for novel, effective methods of 6-O-methyl erythromycin A synthesis.
Previously developed methods attempt to achieve 6-O-methyl erythromycin synthesis via the following methods.
European Patent No. 0 272 110 discloses a process for making 6-O-methyl erythromycin A via a bis-TMS, 9-cyclohexyl ketal oxime. The ketal reagent is used in the presence of formic acid and in acetonitrile to form a protected 9-oxime-erythromycin A derivative.
European Patent No. 0 180 415 discloses a process using 9-benzyl oxime derivatives to form the 6-O-methyl erythromycin product. A substituted aryl chloride reagent is used to protect the 9-oxime and removed with palladium catalyst and hydrogen after methylation of the 6-position.
U.S. Pat. No. 4,311,803 discloses preparation of 6-O-methyl erythromycin A involving protection of 2'-hydroxyl and 3'-dimethylamino groups. The process involves using benzyloxycarbonyl (cbz) for protection of the 2'-hydroxyl and 3'-dimethylamino groups. The 3'-dimethylamino group must be regenerated by reductive N-methylation after removal of the cbz protecting group.
European Patent No. 0 195 960 discloses a process of synthesis for 6-O-methyl erythromycin A requiring a quaternary salt. An aryl chloride reacts with a 9-oxime derivative to form a quaternary salt. The salt is subsequently eliminated after 6-O-methylation.
There continues to be a need to provide a rapid, efficient method of producing 6-O-methyl erythromycin compounds that uses mild, neutral synthetic conditions and to provide novel intermediates useful in the production of 6-O-methyl erythromycin derivatives.